CN101035536A

CN101035536A - Combination of organic compounds

Info

Publication number: CN101035536A
Application number: CNA200580033958XA
Authority: CN
Inventors: B·布尔凯; T·E·休斯
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2004-10-08
Filing date: 2005-10-06
Publication date: 2007-09-12
Also published as: JP2008515905A; MX2007004021A; RU2007116869A; BRPI0516446A; US20080070922A1; CA2580266A1; EP1802308A1; AU2005294320A1; WO2006041976A1; KR20070099527A

Abstract

The present invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising; i) DPP IV inhibitor or a pharmaceutically acceptable salt thereof, and ii) at least one PDGF receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof. The present invention furthermore relates to the use of such a combination for the prevention, delay of progression or treatment of a disease or condition selected from insulin resistance, impaired glucose metabolism (IGT), conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, diabetes particularly type 1 or type 2 diabetes mellitus, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, coronary heart disease, hypertension, angina pectoris, myocardial infarction, stroke, vascular restenosis, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance, and vascular events, cardiovascular morbidity or mortality associated with diabetes (e.g. type I or II) or IGT.

Description

The combination of organic compound

The present invention relates to combination, for example combination preparation or pharmaceutical composition, it comprises DPP-IV inhibitor or its officinal salt and at least a pdgf receptor tyrosine kinase inhibitor or its officinal salt respectively.

Found to comprise at least a pdgf receptor tyrosine kinase inhibitor (for example as hereinafter definition) at present and had useful effect, and be applicable to disease that treatment can suppress by the pdgf receptor tyrosine kinase or disease and the disease/disorder that can pass through the DPP-IV suppression therapy as the combination of the DPP-IV inhibitor of common medicament (co-agent) (for example as hereinafter definition).

Therefore the present invention at first relates to combination, for example combination preparation or pharmaceutical composition, and it comprises as active ingredient respectively:

I) DPP-IV inhibitor or its officinal salt and

Ii) at least a pdgf receptor tyrosine kinase inhibitor or its officinal salt.

Preferred composition is the pharmaceutical preparation of pharmaceutical composition or combination.

In this pharmaceutical composition, combination partner (i) and (ii) administration together, in the unit dosage forms of a combination or individually dosed or administration one by one in two independent unit dosage forms.Unit dosage forms also can be fixed combination.

Term " at least a therapeutic agent " should refer to except that DPP IV inhibitor, specified one or more (for example two kinds, three kinds) active ingredients according to the present invention capable of being combined.

This paper uses term " DPP-IV " to be intended to represent DPP IV, is also referred to as CD26.DPP-IV---belong to the serine protease of the amino dipeptidase in proline/alanine cutting back, have from position 2 on the protein of proline or alanine and remove two N terminal amino acids specifically.Because the substrate of DPP-IV comprises insulinotropic hormone glucagon-like-peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), it can be used for controlling glucose metabolism.It is active that GLP-1 and GIP have only complete form to be only; Remove two N terminal amino acids and make its inactivation.

The synthetic inhibitor of using DPP-IV in the body has stoped the N end degraded of GLP-1 and GIP, thereby causes the insulin secretion of the higher plasma concentration of these hormones, raising and improve glucose tolerance.

Term " DPP-IV inhibitor " is intended to expression and shows that DPP-IV and function relevant enzyme suppress (for example from 1-100% inhibition) and keep the molecule of the effect of substrate molecule, described substrate molecule to include but are not limited to GLP-1, GIP, PHM (peptide histidine methionine), P material, neuropeptide tyrosine specifically and other are usually at second molecule that contains alanine or proline residue of aminoterminal.Handle the level that has prolonged the persistent period of peptide substrates effect and improved they complete undegradable forms with the DPP-IV inhibitor, described form causes and the relevant biological activity spectrum of disclosure invention.

For this reason, test compounds suppresses the ability of the CD26/DPP-IV enzymatic activity of purification.In brief, its activity of ability in-vitro measurements of synthesizing substrate glycine-proline-p-Nitraniline. (Gly-Pro-pNA) by the CD26/DPP-IV cutting.DPP-IV cuts Gly-Pro-pNA releasing product p-Nitraniline. (pNA), and it produces speed and is directly proportional with enzymatic activity.Slow down the generation of pNA by special enzyme inhibitor inhibitory enzyme activity.Stronger interaction causes that lower pNA produces speed between inhibitor and the enzyme.The factor, the inhibition degree of pNA accumulation rate is the direct tolerance of enzyme inhibition strength.Accumulate by spectrophotometer measurement pNA.By enzyme and the inhibitor of some variable concentrations and the inhibition constant K i that the substrate incubation is measured every kind of chemical compound with fixed amount.

" DPP-IV inhibitor " also is intended to comprise active metabolite and prodrug thereof, for example active metabolite of DPP-IV inhibitor and prodrug in this paper context.The reactive derivative of the DPP-IV inhibitor that active " metabolite " produces when being the metabolism of DPP-IV inhibitor." prodrug " be metabolism be DPP-IV inhibitor or metabolism for the chemical compound of the identical metabolite of DPP-IV inhibitor.

The DPP-IV inhibitor is known in this field.For example, the DPP-IV inhibitor generally and clearly is disclosed in each case among WO 98/19998, DE19616 486 A1, WO 00/34241, WO95/15309, WO 01/72290, WO01/52825, WO 9310127, WO 9925719, WO 9938501, WO 9946272, WO 9967278 and the WO 9967279.

Preferred DPP-IV inhibitor is described in the following patent application: WO 02053548 (particularly chemical compound 1001 to 1293 and embodiment 1 to 124), WO 02067918 (particularly chemical compound 1000 to 1278 and 2001 to 2159), WO 02066627 (the particularly embodiment of Miao Shuing), (particularly example I is to LXIII and middle all chemical compounds clearly listed and the corresponding analogs of description for WO 02/068420, preferred chemical compound for the report IC50 table in describe 2 (28), 2 (88), 2 (119), 2 (136)), WO 02083128 (particularly embodiment 1 to 13), US2003096846 (the particularly chemical compound of clearly describing), WO 2004/037181 (particularly embodiment 1 to 33), WO 0168603 (the particularly chemical compound of embodiment 1 to 109), EP1258480 (the particularly chemical compound of embodiment 1 to 60), WO 0181337 (particularly embodiment 1 to 18), WO 02083109 (particularly embodiment 1A is to 1D), WO 030003250 (the chemical compound of embodiment 1 to 166 particularly, most preferably 1 to 8), WO 03035067 (the particularly chemical compound of describing among the embodiment), WO 03/035057 (the particularly chemical compound of describing among the embodiment), US2003216450 (particularly embodiment 1 to 450), WO 99/46272 (claim 12 particularly, 14,15 and 17 chemical compound), WO 0197808 (the particularly chemical compound of claim 2), WO 03002553 (the particularly chemical compound of embodiment 1 to 33), WO 01/34594 (the particularly chemical compound of embodiment 1 to 4 description), WO 02051836 (particularly embodiment 1 to 712), EP1245568 (particularly embodiment 1 to 7), EP1258476 (particularly embodiment 1 to 32), US 2003087950 (the particularly embodiment of Miao Shuing), WO 02/076450 (particularly embodiment 1 to 128), WO 03000180 (particularly embodiment 1 to 162), WO 03000181 (particularly embodiment 1 to 66), WO 03004498 (particularly embodiment 1 to 33), WO 0302942 (particularly embodiment 1 to 68), US 6482844 (the particularly embodiment of Miao Shuing), WO 0155105 (the particularly chemical compound of listing among the embodiment 1 and 2), WO 0202560 (particularly embodiment 1 to 166), WO 03004496 (particularly embodiment 1 to 103), WO 03/024965 (particularly embodiment 1 to 54), WO 0303727 (particularly embodiment 1 to 209), WO 0368757 (particularly embodiment 1 to 88), (particularly embodiment 1 to 72 for WO 03074500, embodiment 4.1 to 4.23, embodiment 5.1 to 5.10, embodiment 6.1 to 6.30, embodiment 7.1 to 7.23, embodiment 8.1 to 8.10, embodiment 9.1 to 9.30), WO 02038541 (particularly embodiment 1 to 53), (particularly embodiment 1 to 293 for WO 02062764, the chemical compound 2-{{3-(aminomethyl) of preferred embodiment 95-4-butoxy-2-neopentyl-1-oxygen-1,2 dihydros-6-isoquinolyl } oxygen } acetamide hydrochloride), (particularly embodiment 1-1 is to 1-109 for WO 02308090, embodiment 2-1 is to 2-9, embodiment 3, embodiment 4-1 is to 4-19, embodiment 5-1 is to 5-39, embodiment 6-1 is to 6-4, embodiment 7-1 is to 7-10, embodiment 8-1 is to 8-8, the 90th page of embodiment 7-1 is to 7-7, the the 91st to 95 page of embodiment 8-1 is to 8-59, embodiment 9-1 is to 9-33, embodiment 10-1 is to 10-20), (particularly chemical compound 1 to 115 for US 2003225102, the chemical compound of embodiment 1 to 121, preferred compound is a) to z), aa) to az), ba) to bz), ca) to cz) and da) to dk)), WO 0214271 (particularly embodiment 1 to 320) and US 2003096857 and WO 2004/052850 (particularly for example the chemical compound clearly described of embodiment 1 to 42 and the chemical compound of claim 1), DE 102 56 264 A1 (particularly for example the chemical compound described of embodiment 1 to 181 and the chemical compound of claim 5), WO 04/076433 (the chemical compound of clearly describing particularly, as listed in the Table A, listed chemical compound among the preferred table B, preferred compound I is to XXXXVII, or the chemical compound of claim 6 to 49), WO 04/071454 (the chemical compound of clearly describing particularly, for example chemical compound 1 to 53 or Table I a are to the chemical compound of If, or the chemical compound of claim 2 to 55), WO 02/068420 (the chemical compound of clearly describing particularly, for example Compound I is to LXIII or Beispiele I and analog 1 to 140 or Beispiele 2 and analog 1 to 174 or Beispiele3 and analog 1, or Beispiele 4 to 5 or Beispiele 6 and analog 1 to 5, or Beispiele7 and analog 1-3, or Beispiele 8 and analog 1, or Beispiele 9, or Beispiele 10 and analog 1 to 531, the more preferably chemical compound of claim 13), WO 03/000250 (the chemical compound of clearly describing particularly, for example chemical compound 1 to 166, the chemical compound of preferred embodiment 1 to 9), WO 03/024942 (the chemical compound of clearly describing particularly, for example chemical compound 1 to 59, the chemical compound of table 1 (1 to 68), claim 6,7,8,9 chemical compound), WO 03024965024942 (the chemical compound of clearly describing particularly, for example chemical compound 1 to 54), Wo03002593 (the chemical compound of clearly describing particularly, the chemical compound of table 1 or claim 2 to 15 for example), WO03037327 (the chemical compound of clearly describing particularly, the chemical compound of embodiment 1 to 209 for example), WO03/000250 (the chemical compound of clearly describing particularly, for example chemical compound 1 to 166, the chemical compound of preferred embodiment 1 to 9), WO 03/024942 (the chemical compound of clearly describing particularly, for example chemical compound 1 to 59, the chemical compound of table 1 (1 to 68), claim 6,7,8,9 chemical compound), WO 03024965024942 (the chemical compound of clearly describing particularly, for example chemical compound 1 to 54), Wo03002593 (the chemical compound of clearly describing particularly, the chemical compound of table 1 or claim 2 to 15 for example), WO03037327 (the particularly chemical compound of clearly describing, for example chemical compound of embodiment 1 to 209), WO0238541, WO0230890.

WO 03/000250 (the chemical compound of clearly describing particularly, for example chemical compound 1 to 166, the chemical compound of preferred embodiment 1 to 9), WO 03/024942 (the chemical compound of clearly describing particularly, for example chemical compound 1 to 59, the chemical compound of table 1 (1 to 68), embodiment 6,7,8,9 chemical compound), WO 03024965 (the chemical compound of clearly describing particularly, for example chemical compound 1 to 54), WO 03002593 (the chemical compound of clearly describing particularly, the chemical compound of table 1 or claim 2 to 15 for example), WO03037327 (the chemical compound of clearly describing particularly, the chemical compound of embodiment 1 to 209 for example), WO0238541 (the chemical compound of clearly describing particularly, the chemical compound of embodiment 1 to 53 for example), WO 03/002531 (the chemical compound of clearly describing particularly, preferred the 9th to the 13 page of chemical compound of listing, the chemical compound of most preferred embodiment 1 to 46, the chemical compound of more preferred embodiment 9), U.S. Patent number 6,395,767 (the chemical compounds of preferred embodiment 1 to 109, the chemical compound of most preferred embodiment 60), the U. S. application series number 09/788,173 (agent's file LA50) (the particularly embodiment of Miao Shuing) that submit to February 16 calendar year 2001, WO99/38501 (the particularly embodiment of Miao Shuing), W099/46272 (the particularly embodiment of Miao Shuing) and DE19616 486 A1 (val-pyr particularly, the valyl Thiazolidine, isoleucyl-thiazolidine, the isoleucyl-pyrrolidine, trans-isomerism salt with isoleucyl-thiazolidine and isoleucyl-pyrrolidine).

Other preferred DPP-IV inhibitor comprise U.S. Patent number 6124305 and US 6107317, international patent application book publication number WO 9515309 and WO 9818763 disclosed specific embodiments.

Under each situation (end product of particularly claimed chemical compound and work embodiment), the main component of end product, pharmaceutical preparation and claim are introduced the application as a reference.

The patent application WO 9819998 that announces discloses N-(N '-glycyl that replaces)-2-Cyanopyrolidine, particularly 1-[2-[5-cyanopyrimidine-2-yl] amino]-ethylamino] acetyl group-2-cyano group-(S)-pyrrolidine (NVP-DPP728).

Patent application WO 0034241 that announces and the patent US 6110949 that announces disclose adamantyl-amino-acetyl group-2-Cyanopyrolidine and W (glycyl of the replacement)-4-Cyanopyrolidine that N-replaces respectively.Purpose DPP-IV inhibitor specific reference in claim 1 to 4.Particularly chemical compound 1-[[(3-hydroxyl-1-adamantyl has been described in these applications) amino] acetyl group]-2-cyano group-(S)-pyrrolidine (being also referred to as LAF237 or vildagliptin).

The patent application WO 9515309 open aminoacid 2-Cyanopyrolidine amide of announcing are as the DPP-IV inhibitor.The peptide radical derivative of patent application WO 9529691 open alpha-aminoalkyl phosphonic acids (particularly having proline or the dependency structure) diester of announcing.Purpose DPP-IV inhibitor particularly is described in table 1 those in 8.

In WO 01/72290, those that purpose DPP-IV inhibitor is particularly quoted in embodiment 1 and the claim 1,4 and 6.

WO01/52825 discloses (S)-1-{2-[5-cyanopyridine-2 base clearly] amino]-ethyl-ammonia acetyl group]-2-cyano group-pyrrolidine or (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanogen-pyrrolidine.

The patent application WO 9310127 that announces discloses the borate proline that can be used as the DPP-IV inhibitor.Purpose DPP-IV inhibitor is in particular those that quote among the embodiment 1 to 19.

The patent application WO 9925719 that announces discloses sulphostin---by cultivating the DPP-IV inhibitor of streptomycete (Streptomyces) microorganism preparation.

The 4-8 unit heterocycle that the patent application WO 9938501 open N-that announce replace.Purpose DPP-IV inhibitor is in particular those that quote in the claim 15 to 20.

The patent application WO 9946272 open phosphorus-containing compounds of announcing as the DPP-IV inhibitor.Purpose DPP-IV inhibitor is in particular those that quote in the claim 1 to 23.

The DPP-IV prodrug and the inhibitor of patent application WO 9967278 that announces and WO 9967279 open A-B-C forms, wherein C is stable or unsettled DPP-IV inhibitor.

Other preferred DPP-IV inhibitor are the chemical compound of patent application WO 03/057200 at the 14th to 27 page of disclosed formula I, II or III.Most preferred DPP-IV inhibitor is the 28th and 29 page of chemical compound of clearly describing.

Think may be as the DPP-IV inhibitor of realizing using when of the present invention for disclosed any material (quoting as a reference herein) in above-mentioned patent document.

In another embodiment preferred, the DPP-IV inhibitor is N-peptide acyl-O-aroyl azanol or its officinal salt.Aroyl is for example naphthalene carbonyl or unsubstituted or replaced or dibasic benzoyl by lower alkoxy for example, low alkyl group, halogen or preferred nitro list.The peptide base section preferably comprises two aminoacid, for example glycine, alanine, leucine, phenylalanine, lysine or proline, and the peptide base section that wherein is attached directly on the azanol nitrogen-atoms is preferably proline.

Preferably, N-peptidyl-O-aroyl azanol is the compound or pharmaceutically acceptable salt thereof of VII formula

Wherein

J is 0,1 or 2;

R ε ₁Represent the side chain of natural amino acid; With

R ε ₂Represent lower alkoxy, low alkyl group, halogen or nitro.

In highly preferred embodiment of the present invention, N-peptidyl-O-aroyl azanol is the compound or pharmaceutically acceptable salt thereof of VIIa formula.

For example the N-peptidyl-O-aroyl azanol of formula VII and formula VIIa and preparation thereof are described in " J.Enzyme Inhibition 1988 " by H.U.Demuth etc., the 2nd volume, 129-142 page or leaf, particularly 130-132 page or leaf.

Preferred DPP-IV inhibitor is adamantyl-amino-acetyl group-2-Cyanopyrolidine that N-replaces; N (glycyl of replacement)-4-Cyanopyrolidine; N-(N '-glycyl that replaces)-the 2-Cyanopyrolidine; N-aminoacyl Thiazolidine; N-aminoacyl pyrrolidine; L-not-isoleucyl-thiazolidine; L-threo-isoleucyl-pyrrolidine and L-not-the isoleucyl-pyrrolidine; 1-[2-[(5-cyanopyridine-2-yl) amino] ethylamino] acetyl group-2-cyano group-(S)-pyrrolidine and officinal salt thereof.

Preferred DPP-IV inhibitor is Mona Patel and colleague (Expert Opinion InvestigDrugs.2003 Apr; 12 (4): 623-33) at those of the 5th section description, particularly P32/98, K-364, FE-999011, BDPX, NVP-DDP-728 and other, its publication is quoted as a reference at this paper, particularly described DPP-IV inhibitor.

Another preferred inhibitors is WO 2001068603 or the disclosed compd B MS-477118 of U.S. Patent number 6,395,767 (chemical compound of embodiment 60), also be known as (1S, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxyl three ring [3.3.1.1 ^3,7] last of the ten Heavenly stems-the 1-yl)-1-oxygen ethyl]-2-nitrogen assorted bicyclo-[3.1.0] hexane of generation-3-nitrile, benzoate (1: 1) and corresponding free alkali that patent application WO 2004/052850 page 2 formula M describes, (1S as patent application WO 2004/052850 page 3 formula M description, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxyl three ring [3.3.1.1 ^3,7] last of the ten Heavenly stems-the 1-yl)-1-oxygen ethyl]-2-azabicyclic [3.1.0] hexane-3-nitrile (M ') and monohydrate (M ") thereof.Compd B MS-477118 is also known as saxagliptin.

Another preferred inhibitors is disclosed chemical compound GSK23A among the WO 03/002531 (embodiment 9); also be known as (2S, 4S)-1-((2R)-2-amino-3-[(4-mehtoxybenzyl) sulfonyl]-3-methylbutyryl base)-4-pyrrolidines-2-nitrile hydrochlorate.

FE-999011 is described in the 14th page of patent application WO 95/15309, and compound N o.18.

P32/98 or P3298 (CAS number: 251572-86-8) (also be known as 3-[(2S, 3S)-and 2-amino-3-methyl isophthalic acid-oxygen amyl group] Thiazolidine) can be as follows as 3-[(2S, 3S)-and 2-amino-3-methyl isophthalic acid-oxygen amyl group] Thiazolidine and (2E)-2-succinic acid (2: 1) mixture uses

And at WO 99/61431 and Diabetes 1998,47, the name with Probiodrug among the 1253-1258 is described, and is described as Compound P 93/01 by same company.

Other DPP-IV inhibitor very preferably of the present invention are by International Patent Application WO 02/076450 (particularly embodiment 1 to 128) and Wallace T.Ashton (Bioorganic ﹠amp; MedicinalChemistry Letters 14 (2004) 859-863) (the particularly listed chemical compound of chemical compound 1 and table 1 and table 2) described.Preferred chemical compound is the chemical compound 21e (table 1) of following formula:

Other preferred DPP-IV inhibitor are by patent application WO 2004/037169 (particularly embodiment 1 to 48 describe those) and WO 02/062764 (those of embodiment 1 to 293 description particularly, the more preferably chemical compound 3-(amino methyl) of the 7th page of description-2-isobutyl group (isobuthyl)-1-oxygen-4-phenyl-1,2-dihydro-6-isoquinolin Methanamide and 2-{[3-(aminomethyl)-2-isobutyl group-4-phenyl-1-oxygen-1,2-dihydro-6-isoquinolyl] the oxygen base } acetamide) and patent application WO2004/024184 (particularly reference example 1 to 4) description.

Other preferred inhibitors are described by patent application WO 03/004498, and particularly embodiment 1 to 33, the chemical compound of the following formula of describing by embodiment 7 most preferably, and it also is known as MK-0431 or Sitagliptin.

Preferred DPP-IV inhibitor also is described in patent application WO 2004/037181, and particularly embodiment 1 to 33, most preferably the chemical compound of claim 3 to 5 description.

Preferred DPP-IV inhibitor is adamantyl-amino-acetyl group-2-Cyanopyrolidine that N-replaces; N (glycyl of replacement)-4-Cyanopyrolidine; N-(N '-glycyl that replaces)-the 2-Cyanopyrolidine; N-aminoacyl Thiazolidine; N-aminoacyl Cyanopyrolidine; L-not-isoleucyl-thiazolidine; L-threo-isoleucyl-pyrrolidine and L-not-the isoleucyl-pyrrolidine; 1-[2-[(5-cyanopyridine-2-yl) amino] ethylamino] acetyl group-2-cyano group-(S)-pyrrolidine; MK-431 and pharmaceutical salts thereof.

Most preferred DPP-IV inhibitor is selected from [S]-1-[2-(5-cyano group-2-pyridinylamino) ethylamino] acetyl group-2-pyrrolidine nitrile one hydrochlorate; (S)-and 1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine and L-threo-isoleucyl-thiazolidine be (as mentioned above according to the chemical compound coding of Probiodrug: P32/98); MK-0431; 3-(aminomethyl)-2-isobutyl group-1-oxygen-4-phenyl-1; 2-dihydro-6-isoquinolin Methanamide and 2-{[3-(aminomethyl)-2-isobutyl group-4-phenyl-1-oxygen-1,2-dihydro-6-isoquinolyl] the oxygen base } acetamide and optional pharmaceutical salts thereof.

1-{2-[(5-cyanopyridine-2-the yl of preferred especially following formula) amino] ethylamino } acetyl group-2 (S)-cyano group-pyrrolidine dihydrochloride (DPP728; be also referred to as [S]-1-[2-(5-cyano group-2-pyridinylamino) ethylamino] acetyl group-2-pyrrolidine nitrile one hydrochloric acid) salt, particularly its dihydrochloride and mono-hydrochloric salts:

And the 1-[(3-of following formula hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-, the amino that (S) (is also referred to as (S)-1-[(3-hydroxyl-1-adamantyl)] and acetyl group-2-cyano group-pyrrolidine, LAF237 or vildagliptin):

And the L-threo-isoleucyl-thiazolidine is (as mentioned above according to the chemical compound of Probiodrug coding: P32/98), MK-0431, GSK23A, saxagliptin, 3-(aminomethyl)-2-isobutyl group-1-oxygen-4-phenyl-1,2-dihydro-6-isoquinolin Methanamide and 2-{[3-(aminomethyl)-2-isobutyl group-4-phenyl-1-oxygen-1,2-dihydro-6-isoquinolyl] the oxygen base } acetamide and optional pharmaceutical salts thereof.

DPP728 and vildagliptin clearly disclose at the embodiment 3 of WO 98/19998 and the embodiment 1 of WO00/34241 respectively.DPP-IV inhibitor P32/98 (seeing above) clearly is described in Diabetes 1998,47,1253-1258.DPP728 and LAF237 can be as preparations as described in the 20th page of WO 98/19998 or WO 00/34241 or the international patent application no EP2005/000400 (application number).

The active DPP-IV inhibitor of special preferred oral.

Think may be as the DPP-IV inhibitor of realizing using when of the present invention for disclosed any material (quoting as a reference herein) in above-mentioned patent document or scientific publication thing.

Under each situation (the particularly end product of chemical compound of Yao Qiuing and work embodiment), the theme of end product, pharmaceutical preparation and claim are introduced the application with reference to these publications.

The DPP-IV inhibitor that will use separately according to the present invention can be united use with carrier.

The active DPP-IV inhibitor of special preferred oral.

Term " at least a " should refer to except that renin inhibitor capable of being combined according to the present invention specified one or more (for example two kinds and three kinds) active component.

Tyrosine kinase inhibitor PDGF-R-used according to the invention is preferably selected from following chemical compound:

4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide, PDGF-receptor isotype inhibitor, Mahboobi S etc., J.Med.Chem.2002,45:1002-1018 describe and quote as a reference chemical compound at this paper; The pdgf receptor kinase blocker AG1295 of tool CAS 71897-07-9; As KovalenkoM etc., Cancer Res.199454:6106-6114 and Ludewig D etc., Cell Tissue Res.2000,299:97-103 describe and quote as a reference AG1295/96 at this paper; CT52923 (4-(6,7-dimethoxy-4 '-quinazolyl)-N-(3,4-methylene dioxy base benzyl)-1-piperazine thioformamide); RP-1776; GFB-111; Pyrrolo-[3,4-c]-B-carboline-diketone, SU 102 (by the SUGEN exploitation); AG1296 with CAS 146535-11-7; RPR101511A by Aventis Pharma exploitation; CDP 860 and Zvegf3 by the ZymoGenetics exploitation; CP 673451 and PD 170262 from Pfizer; KI 6783 with CAS 190726-45-5 is by the PDGF-R inhibitor of the Kirin Brewery of Japan exploitation; KN 1022 by the Millenium Pharmaceuticals exploitation of the Kyowa Hakko of Japan and the U.S.; AG 13736 by the Pfizer exploitation; CHIR 258 by Chiron Corporation exploitation; From the MLN 518 of MilleniumPharmaceuticals with from the SU 11248 of SUGEN-Pfizer; Lefiunomide; Or its officinal salt.

CT52923 is described in " Synthesis and structure activityrelationships of PDGF receptor phosphorylation inhibitor-1. " such as Matsuno K, 18thSymposium on Medicinal Chemistry; 1998 Nov 25-27; Kyoto, Japan, thePharmaceutical Society of Japan, Division of Medicinal Chemistry, Tokyo, Japan:Abstract 2-P-05.

Cyclic peptide RP-1776 separates from the culture broth of streptomycete KY11784.It is by for example TokiS, and Agatsuma T etc. is described in J.Antibiot. (Tokyo) 2001 May; 54 (5): 405-14.

GFB-111 is described in Blaskovich MA etc., Nat.Biotechnol.2000Oct; 18 (10): 1065-70 and Delarue F. etc., 91 ^StAnnual meeting of the AmericanAssociation for Cancer research, 41:458,2000.

Pyrrolo-[3,4-c]-B-carboline-diketone is described in Teller S, Eur.J.Med.Chem.2000Apr; 35 (4): 413-27.

CDP 860 is the antibody fragments from the Pegylation of people's antiplatelet derivative growth factor beta receptor antibody.

PD 170262 or 2-[4-(2-diethylamino ethoxy) phenylamino]-8-methyl-6-(3-thienyl) pyrido [2,3-d] pyrimidines-7 (8H)-ketone is effective inhibitor of tyrosine kinase, and the platelet derived growth factor tyrosine kinase is had selectivity.Synthetic and the tyrosine-kinase enzyme inhibition activity of a series of 2-amino-8H-pyrido [2,3-d] pyrimidine for example is described in Klutchko S. etc., 213 ^ThAmericanChemical Society National meeting:abst.MEDI 201 (poster), 1997, USA.

KI 6783 or 4-(3,4-dimethoxy phenoxy group)-6, the 7-dimethoxy-quinoline is described in Kubo K. etc., Bioorganic and Medicinal Chemistry Letters 7:2935-2940,1997 and YagiM. etc., Exp.Cell Research 234:285-92,1997.

The KN1022 or 6 that suppresses the PDGFR phosphorylation, 7-dimethoxy-4 '-[4-(4-nitrobenzophenone) amino carbonyl piperazine-1 base]-quinazoline for example are described in 217 ^ThAmerican Chemical SocietyNational meeting abstr.MEDI 061, Part1,1999, Japan.

AG 013736 or N-methyl-2-[3-[2-(2-pyridine radicals) vinyl]-1H-indazole-6-base sulfenyl]-Benzoylamide for example is disclosed in Heller etc., Pharmacological activities of AG 013736, asmall molecule inhibitor of VEGF/PDGFR tyrosine kinases, 93 ^RdAnnualmeeting f the American association for Cancer research 43:1082,2002, USA.

CHIR 258 is the amino benzo imidazole quinoline growth factor kinase inhibitor of Orally active, and it shows a series of the inhibition activity at (for example from PDGFR family) receptor tyrosine kinase.CHIR 258 is disclosed in 94 respectively by for example Steigerwalt R etc. and Lee SH etc. ^ThAnnualMeeting of the American Association for Cancer Research 753 (plus poster) abstr.3783 and 934 (plus poster) abstr.R4702,2003, USA.

SU11248 or 5-[3-fluoro-2-oxygen-1, the 2-indoline-(3Z)-and ylidenylmethyl]-2,4-dimethyl-1H-pyrroles-3-formic acid (2-diethyllaminoethyl) amine is the inhibitors of kinases of many targets, and for example PDGFR is had selectivity.SU11248 is disclosed in for example Xin L. etc., 93 ^RdAnnual Meeting of theAmerican Association for Cancer Research 43:1081 (plus poster), 2002, USA.

MLN 518 is formula 4-[4-(N-right-different-propoxyl group phenyl amino formoxyl)-1-piperazinyls]-Piperazino derivs of 6-methoxyl group-7-(piperidino propoxyl group)-quinazoline; it suppresses for example in conjunction with PDGF R phosphorylation in measuring; it is described in for example Stone RM etc.; Blood 102:65-66; 2003; KellyLM etc., Cancer Cell 1:421-23,2002.

Come fluorine Lip river rice (SU 101) or the different  azoles of 4-Methanamide, 5-methyl-N-[4-(trifluoromethyl) phenyl] be tyrosine kinase inhibitor.

Preferred pdgf receptor tyrosine kinase inhibitor is that it is quoted as a reference at this paper as the N-phenyl-2-pyrimidine-amine derivatives of the formula II of patent application EP 0 564 409 A1 and WO 99/03854 description.

Preferred above-mentioned all, the chemical compound of (II) formula particularly, it is CGP 57148B{N-{5-[4-(4-methyl-Piperazino-methyl)-benzoyl acylamino-]-the 2-aminomethyl phenyl-4-(3-pyridine radicals)-2-pyrimidine-amine." Imatinib " [international generic name]) and uses thereof (hereinafter: (particularly as antitumor agent) is described among the embodiment 21 of the European patent application EP-A-0564 409 that is published on October 6th, 1993 CGP 57148B, and many other countries be equal to the application and patent in, for example United States Patent (USP) 5,521,184 and Japan Patent 2706682.Another is preferably 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino of the European Patent Application No. of announcing on May 10th, 2,000 998 473) phenyl]-the Benzoylamide mesylate.

Term " 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide " comprise all crystal forms, the beta-crystalline form described of European Patent Application No. 998 473 particularly.

Very preferably use the N-phenyl-2-pyrimidine-amine derivatives of (II) formula with single mesylate salt form.

The chemical compound of II formula generally and clearly is disclosed in patent application EP 0 564 409 A1 and WO99/03854; the end product of particularly claimed chemical compound and work embodiment, the theme of end product, pharmaceutical preparation and claim are introduced the application with reference to these publications.Comprise corresponding stereoisomer and corresponding polymorph equally, for example wherein disclosed crystal changes.

Compound I I is described as can be used for treating cancer, thrombosis, psoriasis, cellulosic generation, scleroderma and atherosclerosis in EP 0 564 409 A1.

For the purpose of isolated or purified, and under the situation of the chemical compound that also is used as intermedium, also may use officinal salt.Yet have only pharmaceutically useful, avirulent salt to be used for the treatment of purpose, therefore preferred these salt.

Other suitable pdgf receptor tyrosine kinase inhibitors are disclosed in WO 98/35958 (the particularly chemical compound of embodiment 62) and US 5,093,330, under each situation (the particularly end product of chemical compound of Yao Qiuing and work embodiment), the theme of end product, pharmaceutical preparation and claim are introduced the application with reference to these publications.

Other preferred chemical compounds are described in patent application WO 04/005281, particularly embodiment, the following formula: compound of most preferred embodiment 92:

It also is known as 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide.

Preferred pdgf receptor tyrosine kinase inhibitor is selected from 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide (imatinib), 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-the Benzoylamide mesylate, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide, (4-(6 for CT52923,7-dimethoxy-4 '-quinazolyl)-N-(3, the 4-Methylenedioxybenzyl)-1-piperazine thioformamide), RP-1776, GFB-111, pyrrolo-[3,4-c]-B-carboline-diketone, SU 102 (by the SUGEN exploitation), AG1296 (CAS 146535-11-7), AG1296 (CAS 71897-07-9) and RPR101511A or its officinal salt under each situation.

Also comprise its officinal salt at (for example chemical compound does not exist with the officinal salt of itself under the hydrochlorothiazide situation) these chemical compounds under each suitable situation.

Corresponding active component or its officinal salt also can solvate form thereof (for example hydrate) use or comprise that other solvents are used for crystallization.

Most preferred pdgf receptor tyrosine kinase inhibitor is { N-{5-[4-(4-methyl-Piperazino-methyl)-benzoyl acylamino-]-2-aminomethyl phenyl }-4-(3-pyridine radicals)-2-pyrimidine-amine } (imatinib) and 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide or under each situation its officinal salt, as mono-hydrochloric salts.

Preferred compositions, for example combination preparation or pharmaceutical composition, it comprises DPP-IV inhibitor (preferred LAF237) or its officinal salt respectively and as the activating agent of second activating agent, described second activating agent is selected from 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide (imatinib), 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-the Benzoylamide mesylate, (4-(6 for CT52923,7-dimethoxy-4 '-quinazolyl)-N-(3,4-methylene dioxy base benzyl)-1-piperazine thioformamide), 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide, RP-1776, GFB-111, pyrrolo-[3,4-c]-B-carboline-diketone, SU 102 (by the SUGEN exploitation), AG1296 (CAS 146535-11-7), AG1296 (CAS 71897-07-9) and RPR101511A, or under each situation its officinal salt.

The chemical compound that makes up can exist by officinal salt.If these chemical compounds have for example at least one basic center, it can form acid-addition salts.Also can form the acid-addition salts of the other basic center of corresponding existence when needing.Chemical compound with acidic-group (for example COOH) also can form salt with alkali.

All these market-oriented products can be used for for example according to combined therapy of the present invention.

Can derive from the current edition of standard summary " Merck index " or derive from the data base such as international monopoly (for example IMS World Publications) by the structure general or activating agent that trade (brand) name is identified.Its corresponding contents is quoted as a reference at this paper.Based on these references, any those skilled in the art fully can the identified activity agent and can be made equally and detection of drugs indication and character in the external or body in the code test model.

More surprisingly following experiment is found: combined administration DPP IV inhibitor or its salt and at least a pdgf receptor tyrosine kinase inhibitor not only cause useful (particularly collaborative) curative effect, and cause the other benefit that produced by combined therapy and compare more wonderful useful effect with the monotherapy that only uses one of combined traditional Chinese medicine thing reactive compound disclosed herein.

Can prove that the combination of DPP-IV inhibitor and at least a pdgf receptor tyrosine kinase inhibitor causes more effectively prevention or the hereinafter specified disease of preferred therapeutic by the test model of determining (test model particularly described herein).Concrete, can show that combination of the present invention causes more effectively prevention or the hereinafter specified disease of preferred therapeutic by the test model of determining (test model particularly described herein).

If take place simultaneously, this result not only causes useful (particularly working in coordination with) curative effect of further reinforcement, and causing the additive effect that produces by treatment simultaneously, multiple combination for example described herein is to pancreas β cell, diabetes (for example I type or type ii diabetes), IGT, obesity and vascular events, cardiovascular diseases or the sickness rate wonderful effectiveness prolongation related with diabetes or IGT, more various treatment therapy and wonderful beneficial effect.

Term " enhancing " is meant and improves corresponding pharmaceutically active or therapeutic effect respectively.Strengthen a kind of composition according to combination of the present invention according to another composition according to the present invention and be meant the bigger effect of effect that is reached when reaching by using jointly than independent a kind of composition.

Produce total synergy when term " collaborative " should refer to common drug administration, it is greater than the summation of every kind of independent application effect of medicine.

In addition, for people patient (particularly old people), for example remember to take simultaneously two kinds of tablets than staggered using (promptly according to more complicated treatment time table) is more convenient and simple in time in ante cibum.More preferably, two kinds of active component are used as fixed combination under all situations described herein, promptly as single tablet.Take single tablet and take two easier operations of tablet than simultaneously.In addition, also easier the finishing of packing.

Various equivalent modifications can select the animal test model of relevant and standard to prove above and therapeutic effect of hereinafter pointing out and useful effect fully.

Can prove by for example using the known corresponding pharmacology model of association area by the pharmaceutical active of using activating agent combination realization used according to the invention.

The characteristic that strengthens insulin secretion according to combination of the present invention can be by basis as Biol.Pharm.Bull.29 such as T.Ikenoue (4), and disclosed method is determined in 354-359 (1997) publication.

The corresponding purport of these lists of references is incorporated herein by reference in this manual.

Therefore, combination according to the present invention can be used for for example preventing, postpones to make progress or treat the disease and the disorder that can suppress and/or pass through to suppress the inhibition of PDGF tyrosine kinase receptor by DPPIV.

Therefore on the other hand, the present invention relates to use combination to be used to make prevention, postpone progress or treatment and can suppress and/or the purposes of medicine by suppressing disease that the PDGF tyrosine kinase receptor suppresses and disorder by DPP IV, described combination comprises

I) DPP IV inhibitor or its officinal salt and

Ii) at least a pdgf receptor tyrosine kinase inhibitor or its officinal salt.

The invention still further relates to and be used to prevent, postpone to make progress, treat disease or disorderly method, described disease or disorder can by DPP IV suppress and/territory suppresses by suppressing the PDGF tyrosine kinase receptor, described method comprises the combination that its homoiothermic animal of needs is used (comprising the people) DPP IV inhibitor or its officinal salt and at least a therapeutic agent or its officinal salt and at least a additional pharmaceutically suitable carrier of common effective dose, and described therapeutic agent is selected from and the interactional medicament of pdgf receptor tyrosine kinase inhibitor.

The invention still further relates to the pharmaceutical composition that is used to prevent, postpone to make progress, treat disease or situation, described disease or situation are selected from and can suppress and/or pass through to suppress disease or the disorder that the PDGF tyrosine kinase receptor suppresses by DPP IV, and described pharmaceutical composition comprises the combination of DPP IV inhibitor or its officinal salt and at least a pdgf receptor tyrosine kinase inhibitor or its officinal salt and at least a additional pharmaceutically suitable carrier.

Method as implied above or purposes, wherein disease or disease are selected from insulin resistance, impaired glucose metabolism (IGT), the impaired glucose tolerance disease, fasting glucose reduces (impaired fastingplasma glucose) disease, diabetes (particularly 1 type or type 2 diabetes mellitus), obesity, diabetic retinopathy, degeneration of macula, cataract, diabetic nephropathy, glomerular sclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, coronary heart disease, hypertension, angina pectoris, myocardial infarction, apoplexy, vascular restenosis, skin and connective tissue disease, ulcer of foot and ulcerative colitis, endothelial dysfunction and arterial compliance are impaired, and vascular events (vascular event), with diabetes (I or II type) or relevant cardiovascular morbidity or the death of IGT.

Most preferably, disease or disease are selected from obesity, diabetes (1 type or type 2 diabetes mellitus), IGT and vascular events, the cardiovascular diseases relevant with diabetes (I or II type) or IGT falls ill or death.

This paper has described the preferred combination that is used for described purposes or method.

" disease or the disease that can be suppressed by the DPP-IV inhibitor " of the application definition comprises (but being not limited only to) insulin resistance, impaired glucose metabolism, the impaired glucose tolerance disease, fasting glucose reduces disease, diabetes (particularly 1 type or type 2 diabetes mellitus), obesity, diabetic retinopathy, degeneration of macula, cataract, diabetic nephropathy, glomerular sclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, coronary heart disease, hypertension, angina pectoris, myocardial infarction, apoplexy, vascular restenosis, skin and connective tissue disease, ulcer of foot and ulcerative colitis, endothelial dysfunction and arterial compliance are impaired.This definition also comprises the useful influence of disease and the disease relevant with diabetes or IGT (for example less weight increase or less vascular events and cardiovascular morbidity or death).

" vascular events " relevant with diabetes of the application definition comprises (but being not limited only to) atherosclerosis, thrombosis, cerebrovascular disease (as apoplexy, ischemia, death and the relevant dementia of apoplexy that apoplexy is relevant), peripheral arterial disease (for example limb ischemia, limping (claudation) or intermittent claudication (intermittent claudation), experience amputation (undergoamputation)), microvascular disease and sequela, as neuropathy, nephropathy and retinopathy; Grand angiopathy is as myocardial infarction, other coronary artery diseases; Cardiac hypertrophy.

" disease or the disease that can be suppressed by the DPP-IV inhibitor " is preferably selected from impaired glucose metabolism, impaired glucose tolerance disease (IGT), fasting glucose and reduces disease, diabetes (particularly 1 type or type 2 diabetes mellitus), obesity, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ulcer of foot and vascular events, cardiovascular morbidity or the death relevant with diabetes or IGT.

" disease or the disease that can be suppressed by the pdgf receptor tyrosine kinase inhibitor " is preferably selected from pernicious or non-neoplasm disease such as chronic myelogenous leukemia, the positive acute leukemia of Philadelphia chromosome and acute myeloid leukaemia, inhibition blood vessel take place; Tumor (for example leukemia, glioma, sarcoma, prostate, colon, mammary gland, lung or oophoroma); Atherosclerosis, thrombosis (being generally the vascular smooth muscle cell disorder); Scleroderma; Psoriasis, restenosis, fibre modification; Hepatic fibrosis or pneumonia; Inductive disease such as bronchiolitis obliterans are transplanted in asthma, prevention; Prevent the cell of some antibacterial such as porphyromonas gingivalis (Porphyromonas gingivalis) to invade; Multiple medicines patience or hypereosinophilic syndrome; Gastrointestinal stromal tumor (GIST); Autoimmune disease particularly is selected from multiple sclerosis, ulcerative colitis, crohn, rheumatoid arthritis and polyarthritis, scleroderma, lupus erythematosus, dermatomyositis, pemphigus, polymyositis, vasculitis and graft versus host disease; Inflammatory diseases, more specifically relevant inflammatory diseases, for example rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis diseases with mastocyte; Diabetic nephropathy and glomerulonephritis, chronic pyelonephritis or IgA nephropathy; Cardiovascular disease or damage, the hypertrophy middle level that is preferably selected from stroke prevention, tremulous pulse and/or the trunk of heart reconstruction, pulmonary congestion and DCM (dilated cardiomyopathy) after cardiac hypertrophy, the myocardial infarction or core fiberization, cardiomyopathy such as DCM (dilated cardiomyopathy) in the hypertrophic neuropathy or hypertrophic neuropathy or diabetic cardiomyopathy, a left side or right ventricular hypertrophy, diabetic myopathy, congestive heart failure thickens, mesentery vascular system hypertrophy or atherosclerosis; Nephropathy or damage for example are selected from the albuminuria as the kidney ultrafiltration behind the portal renal ablation, chronic renal disease, renal artery disease, nephrosclerosis, hypertensive nephrosclerosis or the glomerular mesangium hypertrophy (mesanglial hypertrophy) that hypertension causes.All these purposes are described in some patent applications that relate to pdgf receptor tyrosine kinase inhibitor " Imatinib " by the applicant.

" disease or the disease that can be suppressed by the pdgf receptor tyrosine kinase inhibitor " is preferably selected from diabetic myopathy, diabetic cardiomyopathy, diabetic nephropathy, autoimmune disease, atherosclerosis, cardiovascular disease or damage.

This paper uses term " to have treatment to render a service " and is meant the effectiveness for the treatment of ongoing disease, disorder or disease.

Term " prevention " is meant the generation or the recurrence of disease, disorder or disease that prevention is to be treated.

This paper uses term " to postpone progress " and is meant the patient is used combination, described patient is in disease early stage that must treatment or early stage, wherein patient diagnosis is that the early stage or the patient of corresponding disease is in following situation, under this situation corresponding disease may take place, for example the patient is under the situation that Drug therapy or accident cause.

This paper uses term " pharmaceutical preparation of combination " to be meant that active component (for example imatinib) and DPP-IV inhibitor (preferred LAF237) are as the entity that separates simultaneously, not special time restrictedly to be administered to the patient together or sequentially, wherein this class administration preferably provides the treatment effect level of two kinds of chemical compounds simultaneously in body.For example, revocable combination can be two kinds of capsules that contain a kind of active component separately, and its purpose is to make the co-therapy that reaches two kinds of active component in patient's body.

In this description, term " treatment " comprises prophylactic treatment and healing or the treatment of disease inhibition, comprises that treatment has the risk of catching or suspect having caught or the patient and the sick patient of disease.This term also comprises the treatment that postpones progression of disease.

The therapeutic alliance effective dose of activating agent preferred combined according to the invention can one after the other or with fixed combination be used simultaneously or with any order (pharmaceutical preparation of combination).In some cases, the medicine with different mechanism of action capable of being combined.Yet, only consider to have different model of action but the drug regimen that acts on zone similarity is not to certainly lead to the combination with favourable effect.

More surprisingly following test is found: the combined administration according to its pharmaceutically acceptable form under DPP-IV inhibitor of the present invention and pdgf receptor tyrosine kinase inhibitor or each situation not only produces useful, that particularly strengthen or collaborative therapeutic effect.In addition, can obtain other benefits that combined therapy produces, for example to the effectiveness of prolongation astoundingly of disease relevant and disease, therapeutic treatment and wonderful advantageous effects (for example weightening finish still less or vascular events still less and cardiovascular morbidity or death) more broadly with diabetes.

In addition, during the treatment diabetes, combination of the present invention is specially adapted to adjusting, suppresses or reduces or prevent the necrosis or the programmed cell death of the β cell of β cytopathy, the forfeiture of β cell function, β cellular machine dysfunction and/or β cell death such as diabetics (for example I or II type), and also can increase β cell quality and rejuvenation β cell (growth of stimulation beta cell, differentiation and cell survival).This effect (effect is treated in giving or strengthening of particularly making up) can be passed through from (Diabetes.2003 Mar such as Pospisilik JA; 52 (3): publication 741-50) or the experimental program of being described by patent application US20030220251 and WO0135988 prove.

Therefore the present invention relates to combination on the other hand and be used for making and be used for regulating, suppress or reduce or prevention β cytopathy, the forfeiture of β cell function, β cellular machine dysfunction and/or β cell death (as the necrosis or the programmed cell death of β cell), be used to improve the cell quality and be used for the purposes of the medicine of β rejuvenation cell (particularly the patient who suffers from I for example or type ii diabetes), described combination comprises

I) DPP IV inhibitor or its officinal salt and

Ii) at least a PDGF tyrosine kinase receptor inhibitor or its officinal salt.

The invention still further relates to and be used for regulating, suppress or minimizing or prevention β cytopathy, the forfeiture of β cell function, the necrosis or the programmed cell death of β cellular machine dysfunction and/or β cell death such as β cell, be used to increase the method for cell quality and rejuvenation β cell, it comprises the combination that its homoiothermic animal of needs is used the associating effective dose, described homoiothermic animal comprises the people, the experimenter who preferably suffers from diabetes (for example I or II), the described DPP of being combined as IV inhibitor or its officinal salt and at least a being selected from and pdgf receptor tyrosine kinase inhibitor or the therapeutic agent of the interactional therapeutic agent of its officinal salt and the combination of at least a other pharmaceutically suitable carrier.

The invention still further relates to pharmaceutical composition, it is used to regulate, suppress or reduce or prevent the necrosis or the programmed cell death of β cytopathy, the forfeiture of β cell function, β cellular machine dysfunction and/or β cell death such as β cell, be used to increase β cell quality and rejuvenation β cell, described pharmaceutical composition comprises the combination of DPP IV inhibitor or its officinal salt and at least a pdgf receptor tyrosine kinase inhibitor or its officinal salt and at least a other pharmaceutically suitable carrier.

Disease, disorder or disease relate to diabetes, particularly type 2 diabetes mellitus includes but are not limited to diabetic nephropathy, diabetic retinopathy and diabetic neuropathy, degeneration of macula, coronary heart disease, myocardial infarction, diabetic cardiomyopathy, cardiomyocyte cell death, coronary artery disease, peripheral arterial disease, apoplexy, limb ischemia, vascular restenosis, ulcer of foot, endothelial dysfunction and/or atherosclerosis.

Other benefit can be used for reducing dosage for the single medicine with more low dosage combined according to the invention, and for example dosage not only usually needs still less, and frequency of utilization is lower, or can be used for reducing the incidence rate of side effect.This is according to patient's to be treated expectation and requirement.

Consider the DPP-IV inhibitor or the pdgf receptor tyrosine kinase inhibitor of minimizing dosage used according to the invention, combination exists considerable safety to make it be applicable to first-line treatment.

This paper above and pharmaceutical composition according to the present invention hereinafter described can be used for simultaneously or with any order using in succession, be used for using separately or being used in combination with fixed.

Above described method or purposes, wherein DPP-IV inhibitor and pdgf receptor tyrosine kinase inhibitor are used with combining form of the present invention (as the preparation or the cover medicated bag of fixed combination or combination).

Combination described herein, method or purposes, wherein the DPP-IV inhibitor is (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine, and wherein the pdgf receptor tyrosine kinase inhibitor preferably is selected from 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide (imatinib), 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-the Benzoylamide mesylate, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide, (4-(6 for CT52923,7-dimethoxy-4 '-quinazolyl)-N-(3, the 4-methylenedioxy benzyl)-1-piperazine formyl sulfide amine), RP-1776, GFB-111, pyrrolo-[3,4-c]-B-carboline-diketone, SU 102 (by the SUGEN exploitation); AG1296 (CAS 146535-11-7), AG1296 (CAS 71897-07-9) and RPR101511A, or under each situation its officinal salt.

Aforesaid combination, method or purposes; wherein the DPP-IV inhibitor is (S)-1-{2-[5-cyanopyridine-2 base) amino] ethyl-glycyl)-2-cyano group-pyrrolidine and wherein the pdgf receptor tyrosine kinase inhibitor be 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide or its officinal salt, particularly 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino under each situation) phenyl]-the Benzoylamide mesylate.

According to the present invention, when using DPP-IV inhibitor and pdgf receptor tyrosine kinase inhibitor jointly, it can be in succession or side by side in time that this class is used, usually preferred while method.For sequential application, DPP-IV inhibitor and pdgf receptor tyrosine kinase inhibitor can be used with any order.It is oral that usually preferred this class is used.Especially preferably use is oral and the while.Yet, if the experimenter of treatment can not swallow or buccal absorption is otherwise impaired or do not wish that parenteral or applied dermally will be suitable.When sequential application DPP-IV inhibitor and pdgf receptor tyrosine kinase inhibitor, can use separately by same procedure or distinct methods.

Another aspect of the invention is and be used to prevent, postpone to make progress, treat the medicine box according to disease of the present invention or disease, it comprises

(a) a certain amount of DPP IV inhibitor or its officinal salt in first unit dosage forms;

(b) second (etc.) a certain amount of at least a pdgf receptor tyrosine kinase inhibitor in the unit dosage forms, or under each situation its officinal salt suitably the time; With

(c) be used to hold described first, second (etc.) container of unit dosage forms.

In its modification, the present invention relates to " cover medicated bag " equally, for example means that the component to be made up according to the present invention can be independently or by using different fixed combination and the component of varying number (i.e. while or at different time points) administration.Overlap then the part of medicated bag can be for example simultaneously or stagger in time (promptly for arbitrary part of cover medicated bag with equate or different interval at different time points) use.Preferably, selection time make at interval when being used in combination part to the effect of the disease of treatment or disease greater than when only using any component with the effect that obtains.

Therefore the invention still further relates to the cover medicated bag, it comprises

(b) a certain amount of at least a pdgf receptor tyrosine kinase inhibitor, or its officinal salt suitably time the under each situation, with two or three or the more separation unit form of component (a), be used in particular for prevention, delay progress, treatment according to disease of the present invention or disease to (b).

The invention still further relates to commercial packing, the description that it comprises according to combination of the present invention and about simultaneously, separates or use in succession.

In preferred embodiments, (commerce) product is commercial packing, it comprise as active component according to combination of the present invention (with component (a) or (b) two or three or more separation unit form), and about its when postponing progress or treating disease described herein simultaneously, separate or use in succession or the description of its combination in any.

Described herein all be preferably applied to combination of the present invention, compositions, purposes, Therapeutic Method, " cover medicated bag " and commercial packing.

These pharmaceutical preparatioies for be used for through intestinal (as oral) and rectum or parenteral administration in Homoiotherm, described preparation comprises independent or with the pharmacologically active chemical compounds of pharmacy auxiliary substance commonly used.For example, pharmaceutical preparation is formed to about 80% reactive compound by about 0.1% to 90%, preferred about 1%.Be used for being for example unit dosage forms, for example coated tablet, tablet, capsule or suppository and injection through the pharmaceutical preparation of intestinal or parenteral and ophthalmic administration.These are with known method preparation itself, for example use conventional mixed, granulation, coating, dissolving or freeze drying process.Therefore being used for oral pharmaceutical preparation can followingly obtain: combined activity chemical compound and solid excipient; the mixture that granulation obtains when needing; and in needs or process mixture when essential, or after adding suitable auxiliary substance, make its granule turn to the tablet or the coated tablet heart.

The dosage of reactive compound can be depending on multiple factor, for example method of application, constant temperature species, age and/or individual state.

Active component preferred dosage according to drug regimen of the present invention is the treatment effective dose, particularly can commercial those that obtain.

Usually for oral administration, the patient heavy to about 75kg estimates that roughly daily dose arrives about 360mg for about 1mg.

Pharmaceutical preparation will provide with suitable unit dosage forms (for example capsule or tablet), and comprise with for example 50mg of another associating effective ingredient or the LAF237 of 100mg or 150mg amount.

Pharmaceutical composition according to the present invention as indicated above can be used for using simultaneously or using in succession with any order, uses separately or as fixed combination.

Therefore according to another embodiment, the DPP-IV inhibitor is with preferably using with the form of fixed drug compositions with the interactional activating agent of pdgf receptor tyrosine kinase inhibitor, and described pharmaceutical composition comprises pharmaceutically suitable carrier, carrier or diluent.Therefore, DPP-IV inhibitor of the present invention can be used with oral, the dosage form parenteral or percutaneous of any routine as fixed combination with the pdgf receptor tyrosine kinase inhibitor.

The DPP-IV inhibitor dosage of (I) formula that will use homoiothermic animal (people of for example about 70kg body weight), particularly arrive about 3g for about 3mg to suppressing the effective dosage of DPP-IV enzyme, preferred about 10mg is to about 1g, for example about 20mg preferably is divided into 1 to 4 for example single dose of identical size to 200mg for each person every day.Usually child's half of dosage of accepting to be grown up approximately.Each individual essential dosage can monitor by the serum-concentration of for example measuring active component, and is adjusted to optimal level.Single dose for example comprises 10,40 or the 100mg/ adult patient.

(S)-and 1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine or 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-dosage of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide is preferably between every day 10 to 150mg, most preferably between every day 25 to 100mg or between 25 to 50mg or between every day 50 to 150mg.Every day, the preferred embodiment of oral dose was 25,30,35,45,50,55,60,80,100 or 150mg.Preferred unit dosage forms comprises 25,50,100 or 150mg vildagliptin.As many as every day three times can take place in the using of active component, preferably once a day or twice.

Preferred pdgf receptor tyrosine kinase inhibitor described herein will provide with suitable unit dosage forms (for example capsule or tablet) form, and comprise the treatment effective dose of having described as this paper and prior art (for example about 2 to about 600mg).As many as every day three times can take place in the using of active component, preferably once a day or twice.Select identical preferred dosage to be used for fixing combination.

N-{5-[4-(4-methyl-piperazinyl-methyl)-benzoyl acylamino-]-the 2-aminomethyl phenyl-4-(3-pyridine radicals)-2-pyrimidine-amine list mesylate is preferably with about 2.5 by 850mg/ days, more preferably 5 to 600mg/ days and most preferably 20 to 300mg/ days dosage range be administered to the people.Unless this paper has explanation in addition, this chemical compound is used one to four time preferred every day.Be used to send imatinib (N-{5-[4-(4-methyl-piperazinyl-methyl)-benzoyl acylamino-]-the 2-aminomethyl phenyl-4-(3-pyridine radicals)-2-pyrimidine-amine) or the preferred galenical of its single mesylate be known in this field, for example in patent application WO03/090720.Preferably with 50,10,200,300 or the form of 400mg unit dosage forms use imatinib.

According to combination of the present invention; purposes or method, wherein 50; 100; 200; 300 or 400mg be selected from 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide; 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-the Benzoylamide mesylate; 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pdgf receptor tyrosine kinase inhibitor of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide or each situation under its officinal salt and 50; 100 or 150mg (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine or its officinal salt combined administration give the patient or be administered to the patient every day.

Corresponding dosage can be for example in the morning, noon or use at dusk.

Preferably, under the independent assortment situation, be preferably the dosage of the input product that goes through and put goods on the market.

Special preferred low dose combination.

In order to further specify the present invention but not be used for the restriction, the following example is provided.

Experimental section:

Above-mentioned character proves in can detecting in external or body, uses favourable mammal such as mice, rat, dog, monkey or isolating organ, tissue and prepared product thereof.Described chemical compound can be external with solution (for example preferred aqueous solutions) form, in the body with through intestinal, parenteral, advantageously the form of intravenous (for example suspension or aqueous solution) is used.External dosage can be about 10 ^-5Mole is to 10 ^-10In the molar concentration scope.Intravital treatment effective dose can be depending on route of administration about 1 and 500mg/kg, preferred about 5 and the 100mg/kg scope in.

Detect glycemic control in the mice body

Above-mentioned advantage can experimental results show that by following.(male, in five ages in week, body weight: about 20g) fasting is 18 hours, then as detecting the experimenter for the ICR-CDI mice.Be suspended in separately in the 0.5%CMC-0.14M sodium chloride buffer solution (pH 7.4) according to combination of the present invention (for example LAF237+imatinib (Glivec )) and active component).Thus obtained solution detects the experimenter with Orally administered the giving of fixed volume.Determine reduction percentage ratio behind the Preset Time with respect to matched group blood glucose.

Glucose and insulin active reduce and can followingly assess in the body:

The bull C57BL ob/ob mice in 11 ages in week (Jackson Lab, Bar Harbor, ME) the backlight circular chamber (afternoon 6:00 to the morning 6:00 light is arranged) in six in every cage live and arbitrarily use Purina rodent and water.8:00 got the afterbody blood sample and measured plasma glucose levels first day morning.Animal is assigned randomly to contrast and compound/combination group.The meansigma methods of the plasma glucose value of coupling group.Give the compound/combination (30mg/kg) in animal oral carrier (0.5% carboxymethyl cellulose and 0.2% tween 80) or the carrier then.Mice administration every day is given 3 days altogether.The 4th day, get the base portion blood sample.Use YSI2700 dual pathways biochemical analyzing equipment (Dual Channel BiochemistryAnalyzer) (Yellow Springs Instrument Co., Yellow Springs, OH) concentration of glucose of analysed for plasma sample is also measured insulin concentration with the ELISA algoscopy.

The beta cell effect

Male Zucker Diabetic Fatty fa/fa (ZDF) rat is the type 2 diabetes mellitus model.This rat be glucagon but when birth blood glucose normal and when about age week in 7 weeks to 10, develop into diabetes.Although animal is before diabetes outbreaks and the early stage hyperinsulinism of diabetes, they were lost the insulin secretion that glucose stimulates afterwards and finally became complete basically insulin deficit type.

Above-mentioned advantage can show by following nonrestrictive experience.Usually research be will develop into the time period with tangible type 2 diabetes mellitus from impaired glucose tolerance animal and LAF237 and Imatinib comprised (hereinafter: the therapeutic effect of combination combination " A ").Study three groups of male ZDF mices (Genetic Models Inc, Indianapolis, Ind., USA) and per two days with carrier (A group) LAF237 separately, (B group) Imatinib is independent, (C group) makes up " A " subcutaneous administration, every group of n=6.Animal was 7 to 8 ages in week when administration was initial.Yet they and one group of non-diabetic Sprague-Dawley rat comparative assessment, described Sprague-Dawley rat feeds significantly to be lower than the glucose level of ZDF animal (6.4 ± 0.6vs 5.8 ± 0.8, mean value SD, p＜0.02).ZDF animal glucose tolerance state reduced relatively when this showed the research beginning.

Bromodeoxyribouridine (BrDU) thus mix the cell that among the new synthetic DNA labelling is just being duplicated.Put to death the first six hour and give injection 100mg BrDU/kg in the rat peritoneum.Put to death back fixing pancreas in 4%PFA, dehydration, paraffin embedding is also cut into slices double staining BrDU and insulin to measure the beta-cell proliferation rate with 3-4mm.

With the anti-Cavia porcellus Ig dyeing of Cavia porcellus glucagon, the link coupled rabbit of peroxidase insulin, and develop with AEC and to produce red staining.Also use DAB and CuSO with monoclonal mouse anti BrDU, the anti-mice Ig of biotinylated goat, avidin peroxidase stain BrDU ₄Develop and produce crineous dyeing.With every section more than 1500 painted nucleus of cytoscopy BrDU and the painted Cytoplasm of insulin.The observer did not know the source of cutting into slices when section detected and to carry out.

The rat of handling with combination " A " can show the raising of the dependent dose of β cell fraction, and its cell proliferation owing to irriate mixes BrDU.

Adjacent section must be to insulin and glucagon-somatostatin-pancreatic polypeptide compound staining to measure the relative mass of beta Cell of islet and non-β cell.The insulin of β cell as mentioned above dyes.Non-β cell is with the anti-pancreatic polypeptide mixture dyeing of the anti-somatostatin+rabbit of monoclonal mouse anti glucagon+rabbit, by the anti-many Ig of biotinylated pig, the avidin peroxidase detects and with DAB and CuSO ₄Develop and produce crineous dyeing.The volume fraction of β cell and non-β cell is estimated by three-dimensional (the point counting stereologic) technology of learning of some counting.

The β cell fraction that makes up whole pancreas in the rat of " A " in order to show is significantly higher than the rat of A or the treatment of B group, and different groups must compare together.Can show that combination " A " the treatment back β cell volume with doses (30ng/g) improves, and does not find propagation.This practice should be supported to promote to suppress programmed cell death by the combination of using " A ".

In addition, combination " A " can show by the programmed cell death of measuring free fatty acid (FFA), glucose, sulphanylureas or cytokine induction in the β cell external the special inhibition of β programmed cell cell death.

External test, it is used for characterizing the influence of combination " A " to the inductive β programmed cell of prevention FFA cell death: in brief, as Diabetologia 19,439,1980; Transplantation, 68,597,1999; J.Mol.Med., 77,93,1999, Diabetes 48,1230,1999, J.Bio.Chem.274,18686,1999; Proc.Natl.Acad.Sci.95,2498,1999; .J.Bio.Chem, 273,33501,1998; Diabetologia 42,55,1999 described separation (as rat, mice and people) islets of langerhans, and use or without 0.1-10mM long-chain FFA (2: 1 oleic acid/Palmic acids; Sigma), cultivate with combination " A ".The β cell characteristic that accent is died can as mentioned belowly be analyzed.

External test, it is used for characterizing the influence of combination " A " to prevention glucose or the inductive β programmed cell of sulphanylureas cell death: in brief, can be as J.Bio.Chem, 273,33501,1998 described separation are also cultivated islets of langerhans, and as J.Bio.Chem, 273,33501,1998 described in the 0-30mM glucose incubation to induce programmed cell death.In order to prevent the programmed cell death of glucose induction, islets of langerhans can with combination " A " incubation together.

External test, it is used for characterizing the influence that combination " A " prevents the β programmed cell cell death of cytokine induction: in brief, as Diabetologia 42,55, people and rat Langerhans islet are also cultivated in 1999 described separation.The rat of cytokine induction and people β programmed cell cell death can be as Diabetologia 42,55,1999 described finishing.In order to prevent the β programmed cell cell death of cytokine induction, islets of langerhans can with combination " A " incubation together.The β cell characteristic that accent is died can be as mentioned below and as Diabetologia 42,55,1999 described analyses.

Programmed cell death and inhibition thereof can following method detect: the dna degradation relevant with programmed cell death causes free 3 ' OH chain interruption, its available terminal deoxynucleotidyl transferase mediated dUTP nick end labeling-X3 ' breach end labelling (TUNEL) technology (J Cell Biol 199:493,1992) or use following test kit to detect, described test kit is for example original position cell death detection medicine box; BoehringerMannheim, Mannheim or ApoTag, Oncor, Gaithersburg, Md..Be used to use the preparation of the pancreas section of TUNEL technology dyeing procedure cell death or islets of langerhans culture to be described in (Diabetologia 42:566,1999 and Diabetes 48:738,1999).

Other experimental program also is described in U.S. Patent number 6890905 or WO 2004037277 and the WO0101130A1 that is absorbed in the DPP4 inhibitor.

Although the present invention very at length is described with reference to its some preferred version, other versions that do not depart from the spirit and scope of the contained preferred version of this paper are possible.All lists of references that this paper quotes and patent (U.S. and other countries) are quoted as a reference with its integral body at this.

Claims

1. combination, it comprises:

I) DPP IV inhibitor or its officinal salt and

Ii) at least a pdgf receptor tyrosine kinase inhibitor or its officinal salt.

2. according to the combination of claim 1, it comprises at least a extra pharmaceutically suitable carrier.

3. according to the combination of claim 1 or 2, it is the form of combination preparation or fixed combination.

4. comprise:

I) DPP IV inhibitor or its officinal salt and

The purposes that the combination of ii) at least a pdgf receptor tyrosine kinase inhibitor or its officinal salt is used to produce prevention, delay progress or treats the medicine of disease and disease, described disease and disease can suppress and/or suppress by suppressing the PDGF tyrosine kinase receptor by DPP IV.

5. be used to prevent, postpone to make progress or treat the method for disease and disease, described disease and disease can suppress and/or suppress by suppressing the PDGF tyrosine kinase receptor by DPP IV, described method comprises the combination that its homoiothermic animal that comprises the people of needs is used the associating effective dose, the described combination that is combined as DPP IV inhibitor or its officinal salt and at least a pdgf receptor tyrosine kinase inhibitor and at least a extra pharmaceutically suitable carrier.

6. according to the method or the purposes of claim 5 or 6, wherein said disease or disease are selected from insulin resistance, impaired glucose metabolism (IGT), the impaired glucose tolerance disease, fasting glucose reduces (impaired fasting plasma glucose) disease, diabetes, particularly 1 type or type 2 diabetes mellitus, obesity, diabetic retinopathy, degeneration of macula, cataract, diabetic nephropathy, glomerular sclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, coronary heart disease, hypertension, angina pectoris, myocardial infarction, apoplexy, vascular restenosis, skin and connective tissue disease, ulcer of foot and ulcerative colitis, endothelial dysfunction and arterial compliance are impaired, and vascular events (vascular event), cardiovascular morbidity or the death relevant with diabetes or IGT.

7. comprise:

I) DPP IV inhibitor or its officinal salt and

The purposes of the combination of ii) at least a pdgf receptor tyrosine kinase inhibitor or its officinal salt is used to produce adjusting, inhibition or minimizing or prevention β cytopathy, the forfeiture of β cell function, β cellular machine dysfunction and/or the necrosis or the programmed cell death of β cell death such as β cell, the medicine that is used to increase β cell quality and is used for rejuvenation β cell.

8. be used for regulating, suppress or minimizing or prevention β cytopathy, the forfeiture of β cell function, the necrosis or the programmed cell death of β cellular machine dysfunction and/or β cell death such as β cell, the method that is used to increase β cell quality and is used for rejuvenation β cell, it comprises the combination that its homoiothermic animal that comprises the people of needs is used the associating effective dose, the described DPP of being combined as IV inhibitor or its officinal salt and the combination that is selected from at least a therapeutic agent of the interactional activating agent of pdgf receptor tyrosine kinase inhibitor or its officinal salt and at least a extra pharmaceutically suitable carrier.

9. according to the purposes of claim 7, or method according to Claim 8, wherein Zhi Liao patient is a diabetics.

10. according to the purposes of claim 7, or method according to Claim 8, wherein Zhi Liao patient is type 1 diabetes or type 2 diabetes mellitus patient.

11. according to each the combination of above claim; method or purposes; wherein the DPP-IV inhibitor is selected from (S)-1-{2-[5-cyanopyridine-2 base) amino] ethyl-glycyl)-2-cyano group-pyrrolidine; vildagliptin; MK-0431 (Sitagliptin); GSK23A; saxagliptin; 3-(amino methyl)-2-isobutyl group (isobuthyl)-1-oxygen-4-phenyl-1; 2-dihydro-6-isoquinolin Methanamide and 2-{[3-(amino methyl)-2-isobutyl group-4-phenyl-1-oxygen-1,2-dihydro-6-isoquinolyl] oxo } its officinal salt under acetamide or each situation.

12. according to each combination, method or purposes of above claim, wherein the DPP-IV inhibitor is (S)-1-{2-[5-cyanopyridine-2 base) amino] ethyl-glycyl)-2-cyano group-pyrrolidine or (S)-1-[(3-hydroxyl-1-adamantyl) amino] its officinal salt under acetyl group-2-cyano group-pyrrolidine or each situation.

13. according to each the combination of above claim, method or purposes, wherein the pdgf receptor tyrosine kinase inhibitor is preferably selected from 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide (imatinib), 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-the Benzoylamide mesylate, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide, CT52923, (4-(6,7-dimethoxy-4 '-quinazolyl)-N-(3, the 4-methylenedioxy benzyl)-1-piperazine formyl sulfide amine), RP-1776, GFB-111, pyrrolo-[3,4-c]-B-carboline-diketone, SU 102, AG1296, AG1296 and RPR101511A or under each situation its officinal salt.

14. according to each the combination of above claim, method or purposes, wherein the pdgf receptor tyrosine kinase inhibitor is preferably selected from 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide (imatinib), 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-the Benzoylamide mesylate, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide or its officinal salt under each situation.

15. according to each the combination of above claim; method or purposes; wherein the DPP-IV inhibitor is (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine or its officinal salt, the pdgf receptor tyrosine kinase inhibitor is selected from 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide (imatinib); 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-the Benzoylamide mesylate; 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide or its officinal salt under each situation.

16., wherein use 50 to 600mg to the patient and be selected from 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino every day according to each method or purposes of above claim) phenyl]-Benzoylamide; 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-the Benzoylamide mesylate; 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pdgf receptor tyrosine kinase inhibitor of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide or under each situation its officinal salt and 25 to 150mg (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine or its officinal salt.

17., wherein use 50 to 600mg to the patient and be selected from 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino every day according to each the combination of above claim) phenyl]-Benzoylamide; 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-the Benzoylamide mesylate; 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide or under each situation its officinal salt the pdgf receptor tyrosine kinase inhibitor and wherein 25 to 150mg (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine or its officinal salt.

18., wherein use 50 to the patient every day according to each the combination of above claim; 100; 200; 300 or 400mg be selected from 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide; 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-the Benzoylamide mesylate; 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide or the pdgf receptor tyrosine kinase inhibitor and 50 of its officinal salt under each situation; 100 or 150mg (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine or its officinal salt.

19. according to each the combination of above claim; purposes or method are wherein to patient's combined administration 50; 100; 200; 300 or 400mg be selected from 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-Benzoylamide; 4-(4-methyl piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino) phenyl]-the Benzoylamide mesylate; 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-Benzoylamide or the pdgf receptor tyrosine kinase inhibitor and 50 of its officinal salt under each situation; 100 or 150mg (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine or its officinal salt.

20. according to claim 15,17,18 or 19 combination, it is the form of combination preparation or fixed combination.